Better therapeutics are greatly needed to treat patients infected with trypanosomatid parasites such as <i>Trypanosoma cruzi</i> or <i>Trypanosoma brucei</i>. This report describes 28 new imidazopyridines and triazolopyrimidines with potent and selective antitrypanosomal activity. Drug-like properties were demonstrated in a number of in vitro assays. In vivo efficacy was observed for <b>19</b> and <b>20</b> in acute mouse models of <i>T. cruzi</i> infection. Compounds <b>19</b> and <b>20</b> represent potential leads for new anti-Chagas disease drugs.